Advances in Metabolic Engineering for the Accumulation of Astaxanthin Biosynthesis.

Astaxanthin, a lipophilic carotenoid renowned for its strong antioxidant activity, holds significant commercial value across industries such as feed, food, and cosmetics. Although astaxanthin can be synthesized through chemical methods, it may contain toxic by-products in the synthesized astaxanthin, limiting its application in medicine or functional food. Natural astaxanthin can be extracted from algae, however, the cultivation cycle of algae is relatively longer compared to microorganisms. With the advancement of synthetic biology and metabolic engineering, the method of microbial fermentation has emerged as a promising strategy for the large-scale production of astaxanthin. This article provides a comprehensive overview of the research progress in astaxanthin biosynthesis, highlighting the use of the natural host Xanthophyllomyces dendrorhous, and the heterologous hosts Yarrowia lipolytica and Saccharomyces cerevisiae. Additionally, future research prospects are also discussed.

The Azobis(isobutyronitrile)-Promoted Oxidative Radical α-Cyanation of Imine under Atmospheric O2.

Herein, we report an azobis(isobutyronitrile) (AIBN)-promoted radical α-cyanation of in situ formed imine under atmospheric O2. This oxidative radical addition (ORA) procedure proceeds with the sequential homocleavage of AIBN, extrusion of N2, and capture of O2 toward an O-centered radical, which is converted to a cyano radical by ß-scission. Then, the insertion of the cyano radical into the imine C═N bond forms an aminyl radical, leading to α-cyano imine after 1,2-hydrogen atom transfer (HAT) and H abstraction. Such a transition-metal-free procedure features mild reaction conditions and a broad substrate scope, employing molecular O2 as a clean terminal oxidant.

Li2.9Fe0.9Zr0.1Cl6 as Redox-Active Catholyte for Solid-State Li-Ion Batteries.

Solid electrolytes are one of the key challenges that hinder the commercialization of all-solid-state batteries. Most efforts have been made to advance the development of solid electrolytes as separators, while the development of catholytes, particularly redox-active catholytes, has been less extensively studied. The high loading of catholytes in composite cathodes, while facilitating ionic conduction, drastically decreases the energy density of the battery. Here, we report an alternative strategy to improve the energy density by using Li2.9Fe0.9Zr0.1Cl6 as a redox-active catholyte. With a composite cathode containing uncoated LiCoO2 and Li2.9Fe0.9Zr0.1Cl6, the solid-state cell not only shows excellent rate capability and stable long-term cycling, benefiting from the high ionic conductivity of Li2.9Fe0.9Zr0.1Cl6, but also shows a high cathode specific capacity of ∼153 mAh·g-1. This study broadens the chemical space of the materials design for lithium-ion conductors with redox-active elements (e.g., Fe, Ti, V, and Cr), offering new opportunities to reduce the cost and improve the energy density for all-solid-state batteries.

[Effect analysis of trimethylamine N-oxide and its precursors on susceptibility to pancreatic diseases].

OBJECTIVE: To investigate the causal relationship between trimethylamine N-oxide (TMAO) and its precursors (betaine, carnitine, and choline) and pancreatic diseases based on the Mendelian randomization (MR) method. METHODS: Genome-wide association study data of TMAO, betaine, carnitine, choline, acute pancreatitis (AP), chronic pancreatitis (CP), pancreatic cancer (PC), and circulating immune cell characteristics (white blood cell, lymphocyte, monocyte, neutrophil, eosinophil and basophil) were collected. According to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-MR reporting guidelines, the available genetic variants [single nucleotide polymorphism (SNP)] were strictly screened. The causal relationship between exposure (TMAO and its precursors) and outcomes (pancreatic diseases and circulating immune cell characteristics) was evaluated using inverse variance weighting (IVW), MR-Egger regression and weighted median. The reliability of the results was evaluated by sensitivity analysis based on MR-Egger regression, MR-PRESSO, Cochrane's Q test and leave-one-out method. RESULTS: A total of 36 SNP associated with TMAO and its precursors were included. Five of these were associated with TMAO, 13 with betaine, 12 with carnitine, and 6 with choline. (1) MR analysis showed that TMAO may increase the risk of AP [odds ratio (OR) = 1.100, 95% confidence interval (95%CI) was 1.008-1.200, P = 0.032], and choline may reduce the risk of alcoholic acute pancreatitis (AAP; OR = 0.743, 95%CI was 0.585-0.944, P = 0.015). The analysis results of MR-Egger regression and weighted median were consistent with the IVW results. There is no evidence to support a causal relationship between TMAO and its precursors and the risk of CP and PC. Sensitivity analysis indicated that SNP analyzed by MR showed no heterogeneity and low pleiotropy. The leave-one-out method analysis determined that after excluding any SNP, the effect intervals of the remaining SNP on the results were similar to the overall effect intervals, which suggested the robustness of MR results. (2) There was a positive causal relationship between plasma TMAO level and circulating monocyte count (OR = 1.017, 95%CI was 1.000*-1.034, P = 0.048, * represented that the data was obtained by correcting to 3 decimal places from 1.000 1). The causal effect obtained by MR-Egger regression and weighted median analysis was consistent with the results of IVW. Sensitivity analysis illustrated SNP analyzed by MR showed no heterogeneity and pleiotropy. The leave-one-out method analysis determined that after excluding any SNP, the effect intervals of the remaining SNP on the results were similar to the overall effect intervals, which suggested the robustness of MR results. CONCLUSIONS: TMAO and choline may change the risk of AP, and TMAO may contribute to the increase of circulating monocyte count in AP.

Asiaticoside protects against lung injury induced by intestinal ischemia/reperfusion via the upregulation of FoxM1.

Systemic inflammatory response syndrome and respiratory distress syndrome can be induced by lung injury caused by intestinal ischemia/reperfusion (II/R). There is no effective medical treatment for II/R-induced lung injury. Studies have shown that asiaticoside (AS) protects against lung injury and ischemia/reperfusion injury in several organs. We established a rat II/R damage model and collected lung tissue. Six groups (n = 10) were created: (1) the sham group; (2) the II/R group; (3) the II/R + AS (40) group; (4) the II/R + AS (80) group; (5) the II/R + TST group; and (6) the II/R + AS + TST group. To assess the degree of lung damage induced by II/R, we also evaluated HE staining, the wet/dry ratio, oxidative stress, inflammation and apoptosis in the lung tissues. Our results indicated that the severity of lung injury score, wet/dry ratio, oxidative stress, inflammatory factor expression and amount of apoptosis were greater in the II/R-induced lung injury group than in the sham group. Furthermore, when AS was administered, lung injury, oxidative stress, inflammation and amount of apoptosis in the lung tissues were obviously lower than those in the II/R group. Additionally, compared with that in the sham group, the expression of FoxM1 in the lung tissue in the II/R group was significantly greater, and FoxM1 expression in the lung tissue was significantly greater following AS administration. Compared with the AS alone, the administration of thiostrepton (a FoxM1 inhibitor) and AS exacerbated the lung damage induced by II/R. According to our research, AS prevents the lung damage induced by II/R by reducing oxidative stress, inflammation and apoptosis by activating FoxM1 expression.

Emodin alleviates lung injury via the miR-217-5p/Sirt1 axis in rats with severe acute pancreatitis.

Acute lung injury (ALI) is closely related to high mortality in severe acute pancreatitis (SAP). This study unveils the therapeutic effect and mechanism of miR-217-5p on SAP-associated ALI. The miR-217-5p RNA expression was significantly up-regulated in lipopolysaccharide (LPS)-stimulated primary rat alveolar epithelial type II cells (AEC II) and sodium taurocholate-treated pancreas and lung in SAP rats. miR-217 inhibition protected AEC II from LPS-induced damage by inhibiting apoptosis and reducing the TNF-α, IL-6, and ROS levels. miR-217 inhibition suppressed apoptosis and alleviated mitochondrial damage through mitochondria-mediated apoptotic pathway in vitro. Sirt1 is a direct target of miR-217-5p. Dual-luciferase reporter assay confirmed the binding of miR-217-5p to Sirt1 mRNA 3'-UTR. The rescue experiment identified that the anti-apoptotic, anti-inflammatory, and anti-oxidative effects of miR-217 inhibition were mediated by Sirt1 in vitro. Emodin (EMO) protected AEC II from LPS-induced damage and alleviated pancreatic and lung tissue injuries. EMO exerted similar effects as miR-217 inhibition in vitro and in vivo. The effects of EMO were abolished by miR-217 overexpression. In conclusion, miR-217-5p inhibition exerts protective effects on SAP-ALI in vitro and in vivo by repressing apoptosis, inflammation, and oxidative stress through Sirt1 activation. EMO protects against lung injuries in SAP-associated ALI rats through miR-217-5p/Sirt1 axis.

Tuning collective anion motion enables superionic conductivity in solid-state halide electrolytes.

Halides of the family Li3MX6 (M = Y, In, Sc and so on, X = halogen) are emerging solid electrolyte materials for all-solid-state Li-ion batteries. They show greater chemical stability and wider electrochemical stability windows than existing sulfide solid electrolytes, but have lower room-temperature ionic conductivities. Here we report the discovery that the superionic transition in Li3YCl6 is triggered by the collective motion of anions, as evidenced by synchrotron X-ray and neutron scattering characterizations and ab initio molecular dynamics simulations. Based on this finding, we used a rational design strategy to lower the transition temperature and thus improve the room-temperature ionic conductivity of this family of compounds. We accordingly synthesized Li3YClxBr6-x and Li3GdCl3Br3 and achieved very high room-temperature conductivities of 6.1 and 11 mS cm-1 for Li3YCl4.5Br1.5 and Li3GdCl3Br3, respectively. These findings open new routes to the design of room-temperature superionic conductors for high-performance solid batteries.

Clinicopathological and prognostic significance of TIMP1 expression in gastric cancer: a systematic review and meta-analysis.

BACKGROUND: The research on the associations between tissue inhibitors of metalloproteinase-1 (TIMP1) expression and the clinicopathological characteristics and prognosis of patients with gastric cancer (GC) have resulted in contradictory findings. Exploring the associations between TIMP1 and clinicopathological parameters and the prognosis of GC patients is essential. METHODS: We searched the literature in the databases according to the inclusion and exclusion criteria. Hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the relationships between TIMP1 expression and the clinicopathological parameters and prognosis of GC patients. RESULTS: Nine studies with 1,200 GC patients were included. Our results indicated that TIMP1 expression was not related to sex, age, TNM stage, depth of invasion, lymph node metastasis, or tumor size in GC patients. However, TIMP1 expression was associated with the differentiation of GC. Furthermore, TIMP1 expression was associated with poor prognosis in GC patients. CONCLUSION: TIMP1 expression was related to tumor differentiation and poor prognosis but not sex, age, TNM stage, depth of invasion, lymph node metastasis or tumor size.

Incoherent ultrafast energy transfer in phycocyanin 620 from Thermosynechococcus vulcanus revealed by polarization-controlled two dimensional electronic spectroscopy.

Phycocyanin 620 (PC620) is the outermost light-harvesting complex in phycobilisome of cyanobacteria, engaged in light collection and energy transfer to the core antenna, allophycocyanin. Recently, long-lived exciton-vibrational coherences have been observed in allophycocyanin, accounting for the coherent energy transfer [Zhu et al., Nat. Commun. 15, 3171 (2024)]. PC620 has a nearly identical spatial location of three α84-ß84 phycocyanobilin pigment pairs to those in allophycocyanin, inferring an existence of possible coherent energy transfer pathways. However, whether PC620 undergoes coherent or incoherent energy transfer remains debated. Furthermore, accurate determination of energy transfer rates in PC620 is still necessary owing to the spectral overlap and broadening in conventional time-resolved spectroscopic measurements. In this work, the energy transfer process within PC620 was directly resolved by polarization-controlled two dimensional electronic spectroscopy (2DES) and global analysis. The results show that the energy transfer from α84 to the adjacent ß84 has a lifetime constant of 400 fs, from ß155 to ß84 of 6-8 ps, and from ß155 to α84 of 66 ps, fully conforming to the Förster resonance energy transfer mechanism. The circular dichroism spectrum also reveals that the α84-ß84 pigment pair does not form excitonic dimer, and the observed oscillatory signals are confirmed to be vibrational coherence, excluding the exciton-vibrational coupling. Nodal line slope analysis of 2DES further reveals that all the vibrational modes participate in the energy dissipation of the excited states. Our results consolidate that the ultrafast energy transfer process in PC620 is incoherent, where the twisted conformation of α84 is suggested as the main cause for preventing the formation of α84-ß84 excitonic dimer in contrast to allophycocyanin.

Immunotherapy-relevance of a candidate prognostic score for Acute Myeloid Leukemia.

Background: Acute Myeloid Leukemia (AML) exhibits a wide array of phenotypic manifestations, progression patterns, and heterogeneous responses to immunotherapies, suggesting involvement of complex immunobiological mechanisms. This investigation aimed to develop an integrated prognostic model for AML by incorporating cancer driver genes, along with clinical and phenotypic characteristics of the disease, and to assess its implications for immunotherapy responsiveness. Methods: Critical oncogenic driver genes linked to survival were identified by screening primary effector and corresponding gene pairs using data from The Cancer Genome Atlas (TCGA), through univariate Cox proportional hazard regression analysis. This was independently verified using dataset GSE37642. Primary effector genes were further refined using LASSO regression. Transcriptomic profiling was quantified using multivariate Cox regression, and the derived prognostic score was subsequently validated. Finally, a multivariate Cox regression model was developed, incorporating the transcriptomic score along with clinical parameters such as age, gender, and French-American-British (FAB) classification subtype. The 'Accurate Prediction Model of AML Overall Survival Score' (APMAO) was developed and subsequently validated. Investigations were conducted into functional pathway enrichment, alterations in the gene mutational landscape, and the extent of immune cell infiltration associated with varying APMAO scores. To further investigate the potential of APMAO scores as a predictive biomarker for responsiveness to cancer immunotherapy, we conducted a series of analyses. These included examining the expression profiles of genes related to immune checkpoints, the interferon-gamma signaling pathway, and m6A regulation. Additionally, we explored the relationship between these gene expression patterns and the Tumor Immune Dysfunction and Exclusion (TIDE) dysfunction scores. Results: Through the screening of 95 cancer genes associated with survival and 313 interacting gene pairs, seven genes (ACSL6, MAP3K1, CHIC2, HIP1, PTPN6, TFEB, and DAXX) were identified, leading to the derivation of a transcriptional score. Age and the transcriptional score were significant predictors in Cox regression analysis and were integral to the development of the final APMAO model, which exhibited an AUC greater than 0.75 and was successfully validated. Notable differences were observed in the distribution of the transcriptional score, age, cytogenetic risk categories, and French-American-British (FAB) classification between high and low APMAO groups. Samples with high APMAO scores demonstrated significantly higher mutation rates and pathway enrichments in NFKB, TNF, JAK-STAT, and NOTCH signaling. Additionally, variations in immune cell infiltration and immune checkpoint expression, activation of the interferon-γ pathway, and expression of m6A regulators were noted, including a negative correlation between CD160, m6A expression, and APMAO scores. Conclusion: The combined APMAO score integrating transcriptional and clinical parameters demonstrated robust prognostic performance in predicting AML survival outcomes. It was linked to unique phenotypic characteristics, distinctive immune and mutational profiles, and patterns of expression for markers related to immunotherapy sensitivity. These observations suggest the potential for facilitating precision immunotherapy and advocate for its exploration in upcoming clinical trials.

Mitochondrial biological function and risk of atrial fibrillation and atrial flutter: A 2-sample Mendelian randomization study.

Current research suggests that mitochondrial dysfunction can be a contributing factor in the development of cardiac arrhythmias. In pursuit of elucidating the causal link between the biological functions of mitochondria and the occurrence of atrial fibrillation/flutter, we conducted a 2-sample Mendelian randomization (MR) study. Mitochondrial proteins were selected for exposure in this study. To enhance the accuracy of our study, we selected data on AF/AFL from the FinnGen study and the UK Biobank for MR analysis, respectively. The inverse variance-weighted method was utilized as the primary analysis technique for MR. In addition, we performed a series of sensitivity analyses to detect heterogeneity and horizontal pleiotropy. MR results indicated a significant positive association between NAD-dependent protein deacylase sirtuin-5 and AF/AFL (odds ratio = 1.084, 95% confidence interval: 1.037-1.133, P = 3.679 × 10-4, Adjusted P = .024), with consistent outcomes observed in replication analysis (odds ratio = 1.002, 95% confidence interval: 1.001-1.003, P = 4.808 × 10-4, Adjusted P = .032). NAD-dependent protein deacylase sirtuin-5 can significantly promote the occurrence of AF/AFL, and its specific mechanisms warrant further investigation.

UBA2 SUMOylates NQO1 and promotes the proliferation of hepatocellular carcinoma by modulating the MAPK pathway.

In our previous study, we found that small ubiquitin-related modifier (SUMO)-activating enzyme ubiquitin-associated-2 domain (UBA2) was upregulated in hepatocellular carcinoma (HCC) patients who were insensitive to chemoembolization. In this study, we aimed to investigate the role of UBA2 in HCC progression. Three cohorts were used to evaluate the efficacy of UBA2 as a prognostic factor for HCC. Our results indicated that UBA2 was associated with aggressive clinical behaviors and was a strong indicator of poor prognosis in HCC. In vitro experiments demonstrated that UBA2 accelerated cell growth, invasion, and migration. These results were further supported by in vivo experiments. RNA-sequencing analysis indicated NQO1 as a target of UBA2, with its levels altering following UBA2 manipulation. The results were verified by western blotting (WB) and quantitative PCR. The SUMOplot Analysis Program predicted lysine residue K240 as a modification target of UBA2, which was confirmed by immunoprecipitation (IP) assays. Subsequent mutation of NQO1 at K240 in HCC cell lines and functional assays revealed the significance of this modification. In addition, the oncogenic effect of UBA2 could be reversed by the SUMO inhibitor ML792 in vivo and in vitro. In conclusion, our study elucidated the regulatory mechanism of UBA2 in HCC and suggested that the SUMO inhibitor ML792 may be an effective combinatory treatment for patients with aberrant UBA2 expression.

Clinical value of serum tumor markers in assessing the efficacy of neoadjuvant chemotherapy in advanced ovarian cancer: single-center prospective clinical study.

Objective: This study aimed to assess the clinical importance of various biomarkers, including NLR, CEA, CA199, CA125, CA153, and HE4, through dynamic testing to evaluate the effectiveness of neoadjuvant chemotherapy (NACT) for individuals facing advanced ovarian cancer. This provides valuable information for tailoring treatment plans to individual patients, thereby leading to a more personalized and effective management of individuals facing ovarian cancer. Methods: The levels of NLR, CA125, CA199, CEA, CA153, and HE4 were detected before chemotherapy and after 3 courses of chemotherapy. Patients were categorized into ineffective and effective groups according to the effectiveness of NACT. To evaluate the factors influencing NACT's effectiveness in individuals facing advanced ovarian cancer, receiver operating characteristic (ROC) curves, predictive modeling, and multifactorial regression analysis were employed. Results: In the effective group, the patients' age, maximum tumor diameter, and CEA and HE4 levels of the patients were significantly higher compared to those in the ineffective group (P <.05). Additionally, the difference in HE4 levels before and after treatment between the effective and ineffective groups was statistically significant (P<.05). Multifactorial analysis showed that age and maximum tumor diameter were independent risk factors impacting the effectiveness of NACT in individuals facing advanced ovarian cancer (P<.05). The ROC curve for predicting the effectiveness of NACT in individuals facing advanced ovarian cancer showed a sensitivity of 93.3% for NLR and a specificity of 92.3% for CA199. HE4 emerged as the most reliable predictor, demonstrating a specificity of 84.6% and a sensitivity of 75.3%. The area under the curve of the combined CA125 and HE4 assays for predicting the ineffectiveness of NACT in individuals facing advanced ovarian cancer was 0.825, showcasing a specificity of 74.2% and a sensitivity of 84.6%. Conclusion: The predictive capacity for the effectiveness of NACT in individuals facing advanced ovarian cancer is notably high when considering the sensitivity of NLR and the specificity of CA199. Additionally, the combination of CA125 and HE4 assays can obtain a better predictive effect, which can accurately select patients suitable for NACT, determine the appropriate timing of the interval debulking surgery (IDS) surgery, and achieve a satisfactory tumor reduction effect.

Mechanism Investigation and Clinical Retrospective Evaluation of Qingyi Granules: Pancreas Cleaner About Ameliorating Severe Acute Pancreatitis with Acute Respiratory Distress Syndrome.

Background: Despite its extensive utilization in Chinese hospitals for treating acute pancreatitis (AP) and related acute respiratory distress syndrome (ARDS), the active components and mechanisms underlying the action of Qingyi Granule (QYKL) remain elusive. Methods: This study consists of four parts. First, we used Mendelian randomization (MR) to investigate the causal relationship between AP, cytokine, and ARDS. Next, 321 patients were collected to evaluate the efficacy of QYKL combined with dexamethasone (DEX) in treating AP. In addition, we used UHPLC-QE-MS to determine the chemical constituents of QYKL extract and rat serum after the oral administration of QYKL. The weighted gene coexpression network analysis (WGCNA) method was used to find the main targets of AP-related ARDS using the GSE151572 dataset. At last, a AP model was established by retrograde injection of 5% sodium taurocholate. Results: MR showed that AP may have a causal relationship with ARDS by mediating cytokine storms. Retrospective study results showed early administration of QYKL was associated with a lower incidence of ARDS, mortality, admissions to the intensive care unit, and length of stay in AP patients compared to the Control group. Furthermore, we identified 23 QYKL prototype components absorbed into rat serum. WGCNA and differential expression analysis identified 1558 APALI-related genes. The prototype components exhibited strong binding activity with critical targets. QYKL has a significant protective effect on pancreatic and lung injury in AP rats, and the effect is more effective after combined treatment with DEX, which may be related to the regulation of the IL-6/STAT3 signaling pathway. Conclusion: By integrating MR, retrospective analysis, and systematic pharmacological methodologies, this study systematically elucidated the therapeutic efficacy of QYKL in treating AP-related ARDS, establishing a solid foundation for its medicinal use.

Unraveling the excited-state vibrational cooling dynamics of chlorophyll-a using femtosecond broadband fluorescence spectroscopy.

Understanding the dynamics of excited-state vibrational energy relaxation in photosynthetic pigments is crucial for elucidating the mechanisms underlying energy transfer processes in light-harvesting complexes. Utilizing advanced femtosecond broadband transient fluorescence (TF) spectroscopy, we explored the excited-state vibrational dynamics of Chlorophyll-a (Chl-a) both in solution and within the light-harvesting complex II (LHCII). We discovered a vibrational cooling (VC) process occurring over ∼6 ps in Chl-a in ethanol solution following Soret band excitation, marked by a notable ultrafast TF blueshift and spectral narrowing. This VC process, crucial for regulating the vibronic lifetimes, was further elucidated through the direct observation of the population dynamics of higher vibrational states within the Qy electronic state. Notably, Chl-a within LHCII demonstrated significantly faster VC dynamics, unfolding within a few hundred femtoseconds and aligning with the ultrafast energy transfer processes observed within the complex. Our findings shed light on the complex interaction between electronic and vibrational states in photosynthetic pigments, underscoring the pivotal role of vibrational dynamics in enabling efficient energy transfer within light-harvesting complexes.

Regulation of Microtubule Stability in Pulmonary Microvascular Endothelial Cells in Rats with Severe Acute Pancreatitis: Qingyi Decoction is a Potential CDK5 Inhibitor.

Purpose: Explore the therapeutic effects and regulatory mechanism of Qingyi Decoction (QYD) on severe acute pancreatitis (SAP) associated acute lung injury (ALI). Methods: We identified the constituents absorbed into the blood of QYD based on a network pharmacological strategy. The differentially expressed genes from the GEO database were screened to identify the critical targets of QYD treatment of SAP-ALI. The SAP-ALI rat model was constructed.Some methods were used to evaluate the efficacy and mechanism of QYD in treating SAP-ALI. LPS-stimulated pulmonary microvascular endothelial cell injury simulated the SAP-induced pulmonary endothelial injury model. We further observed the therapeutic effect of QYD and CDK5 plasmid transfection on endothelial cell injury. Results: 18 constituents were absorbed into the blood, and 764 targets were identified from QYD, 25 of which were considered core targets for treating SAP-ALI. CDK5 was identified as the most critical gene. The results of differential expression analysis showed that the mRNA expression level of CDK5 in the blood of SAP patients was significantly up-regulated compared with that of healthy people. Animal experiments have demonstrated that QYD can alleviate pancreatic and lung injury inflammatory response and reduce the upregulation of CDK5 in lung tissue. QYD or CDK5 inhibitors could decrease the expression of NFAT5 and GEF-H1, and increase the expression of ACE-tub in SAP rat lung tissue. Cell experiments proved that QYD could inhibit the expression of TNF-α and IL-6 induced by LPS. Immunofluorescence results suggested that QYD could alleviate the cytoskeleton damage of endothelial cells, and the mechanism might be related to the inhibition of CDK5-mediated activation of NFAT5, GEF-H1, and ACE-tub. Conclusion: CDK5 has been identified as a critical target for pulmonary endothelial injury of SAP-ALI. QYD may partially alleviate microtubule disassembly by targeting the CDK5/NFAT5/GEF-H1 signaling pathway, thus relieving SAP-induced pulmonary microvascular endothelial cell injury.

Dynamic Simulation Research on Microprofile Control Mechanism of Foam in Fractured Media Based on Level Set Method.

Fractured reservoirs are an important source of oil and gas energy. After depletion of production, the production capacity of this reservoir decreases rapidly. Effective profile control is needed to improve the sweep efficiency and reservoir heterogeneity. Foam can solve such problems, but its profile control mechanism is not fully understood. Based on this, this paper uses the level set method to study the microscale control mechanism of foam in fractured media. The results show that artificial fractures and high-permeability microfractures are tighter than natural fractures, the Jamin effect of foam is stronger, and the secondary foaming ability is better. Therefore, the plugging ability of foam to natural fractures is far less than that of foam to artificial fractures and high-permeability microfractures. The larger the fracture opening, the larger the foam volume and the smaller the flow rate. As the opening ratio increases gradually, the generated foam flows more to the natural fractures with a large opening, and the effect of foam blocking large fractures becomes worse. The diversion rate curves of different opening ratios show that the foam has a good profile control effect when the opening ratios are 4:1 and 2:1, and even the diversion rate overturns, while the profile control diversion effect is poor when the opening ratio is 10:1, so it cannot play an effective role in profile control. The foam shows the profile control process of preferentially plugging the high-permeability area and allowing more subsequent fluids to enter the low-permeability area. The research reveals the profile control mechanism of foam on fractured reservoirs from the micro level, which is the supplement and verification of relevant macro research and provides a theoretical basis for the efficient development of fractured reservoirs.

Effects of a Complex Environment on Fatigue and Self-Healing Characterization of Asphalt Composites Containing Rock Asphalt.

In recent years, asphalt pavement has been subjected to varied environmental conditions during its service life, conditions that predispose it to deformation and cracking. To enhance the performance of asphalt pavement, rock asphalt has been selected as a modifier due to its good compatibility with virgin asphalt binder and its ability to improve the fatigue cracking resistance of asphalt mixtures. Although scholars have conducted some studies on rock asphalt mixtures, research on the fatigue and self-healing performance of these mixtures under conditions such as ultraviolet (UV) aging and freeze-thaw remains limited. This paper presents findings from a study that employs a combined fatigue-healing test to assess the impact of such complex environmental factors on the fatigue and self-healing properties of fine aggregate matrix (FAM) mixtures containing three types of rock asphalts, i.e., Buton, Qingchuan (QC), and Uintaite Modifier (UM). The analysis of fatigue-healing test results, grounded in viscoelastic continuum damage (VECD) theory, indicates that rock asphalt can extend the fatigue life of FAM mixtures, albeit with a concomitant decrease in their self-healing capabilities. The study further reveals that UV aging, freeze-thaw, and UV aging-freeze-thaw conditions all led to a diminution in the fatigue and self-healing properties of FAM mixtures. However, FAM mixtures containing rock asphalt demonstrated greater resilience against these reductions. Atomic force microscope (AFM) results indicate that UV aging reduced the number of bee-structures and enlarged their area, whereas the incorporation of rock asphalt enhanced the uniformity of these structures' distribution, thereby improving the fatigue cracking resistance of FAM mixtures. Fourier transform infrared spectroscopy (FTIR) analysis reveals that while UV aging increased the carbonyl and sulfoxide indices within the asphalt binder, rock asphalt is effective in mitigating this effect to a certain degree, thereby enhancing the aging resistance of FAM mixtures.